For low-grade gliomas amenable to complete surgical resection, surgery is generally the first and sole intervention providing excellent control of disease. Total resection is usually feasible for tumors arising in the cerebral hemispheres with reports indicating gross total resection (GTR) in 90% of cerebral hemispheric astrocytomas (25,26,55). Low recurrence rates are reported for both JPA and other astrocytomas after total resection (25,26,55, 56, 57). Data from the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) study of primary surgery in low-grade gliomas indicate 5-year progression-free survival in 92% of children after GTR, ranging from 95-100% for JPAs and gangliogliomas to 80% for grade II diffuse astrocytomas in this age group (58). Resection of tumors involving the dominant medial temporal lobe, motor strip region, or the Broca speech cortex may not be possible without inducing severe neurologic deficits. Partial resection may provide initial intervention for decompression and histopathologic diagnosis.

Low-grade gliomas of the diencephalon are technically challenging due to the deep location and eloquent area; however, contemporary series report successful resection for selected tumors in this region (59, 60, 61, 62, 63, 64, 65, 66). Long-term disease control is typically achieved by total resection; occasional regression of diencephalic JPA after partial resection alone has
been reported (59,65,66). The CCG-POG study notes a progression-free survival after surgery alone of 50-60% for diencephalic tumors, much lower than for lesions originating in the cerebellum or cerebral hemispheres where GTR is more common (58).

Radiation therapy is an established, effective treatment for low-grade gliomas, achieving tumor response and durable disease control in a significant proportion of pediatric cases (Fig. 3.2) (26,56,67, 68, 69, 70). An analysis from Pollack et al. showed improved disease control at 10 years after irradiation following incomplete resection of cerebral hemispheric astrocytomas: 82% progression-free survival with irradiation versus 42% after surgery alone. The same study showed no significant benefit in overall survival (26). A recent phase II prospective study published by Merchant et al. demonstrated excellent event-free survival (87% and 74% at 5 and 10 years, respectively) and overall survival over 90% at 10 years for children treated with three-dimensional (3D) conformal irradiation to the MRI-defined tumor volume (71). These outcomes compared favorably to the literature and have been associated with excellent functional outcomes (72). The decreased volume of normal brain exposed to moderate or high radiation doses using conformal techniques with small margins may significantly decrease some of the serious radiation-induced side effects (72,73). Care must be taken to accurately delineate tumor volumes, addressing white matter tracts in defining the clinical tumor volume (CTV). Merchant et al. suggest a minimal margin (as small as 5 mm) may be adequate for well-demarcated tumors (71). Children’s Oncology Group (COG) is currently examining outcomes with the use of a 5-mm anatomically limited CTV margin around the gross tumor volume (GTV) in a multi-institutional trial.

There are no contemporary data suggesting a benefit to postoperative irradiation for completely resected low-grade astrocytomas. For incompletely resected low-grade astrocytomas, early administration of irradiation may not benefit the patient (74). Current indications for radiation therapy after a near total resection (with imaging evidence of disease residual) include symptoms or signs that might improve with irradiation or postsurgical progression in a location not amenable to safe, definitive second resection. Other factors that are taken into consideration are histological subtype or biology (57,75). Chemotherapy may be advised prior to irradiation for young children or for patients with neurofibromatosis (NF1) or cognitive delay.

Reports from the large CCG-POG low-grade trial confirm previous institutional data suggesting that a significant proportion of incompletely resected astrocytomas remain indolent over 3-5 years; progression-free survival rate at 5 years is 55% after near total or subtotal resection (58). A decision to observe children with residual astrocytoma should involve all subspecialties (neurosurgery, radiation oncology, pediatric oncology) indicating the obligation for regular clinical follow-up and imaging that allows one to comfortably observe a child with the anticipation that treatment can be initiated upon documented tumor progression (55). Such an approach balances the recognized efficacy of radiation therapy with potential toxicities related, in part, to the anatomic location and volume of the tumor and the age of the patient (13,27). Inherent in such an approach is the commitment to intervene appropriately with documented disease progression, including use of primary radiation therapy, additional surgery, or chemotherapy as indicated.

JPAs predominate in hypothalamic and OPTs. Prolonged progression-free survival after irradiation alone for these tumors reflects both the indolent nature of tumors in this site and the efficacy of irradiation. Survival rates in excess of 80% at 10 years after irradiation are common for these tumors (9,73). In thalamic astrocytomas, pilocytic histology is less prevalent; 10-year survival results range from 33% to 60% after therapy (9,71,73,74,76).

Anatomically, diffuse low-grade gliomas are uncommon outside the brainstem in children. Gliomatosis cerebri or bithalamic astrocytomas may represent supratentorial counterparts of the more common infiltrating pontine astrocytomas (76,77). These tumors respond to radiation therapy both symptomatically and by imaging, although recurrence and progression often are apparent within a year (76,77).

Chemotherapy has been used with increasing frequency for low-grade gliomas as a strategy to delay or avoid radiation therapy; less data is available regarding chemotherapy response for progressive disease following irradiation. The use of initial chemotherapy for low-grade gliomas has been studied primarily in centrally located tumors that tend to occur in younger patients and are not amenable to resection. Chemotherapy can provide disease control for months to years, more often achieving stable disease or partial response than complete resolution; most tumors progress within 3-4 years, requiring radiation therapy at that time. The age below which chemotherapy is more appropriate is controversial and dependent on factors such as tumor size and location, presence of NF mutation, or developmental or neurocognitive delays. Packer et al. reported age to be the only significant prognostic factor, with 3-year progression-free survival rate of 74% for children ≤5 years old versus 39% for older children (78). In COG, the age of ≤10 years has been chosen for trial eligibility in studies evaluating chemotherapy as initial treatment (79). Individual centers have used thresholds of <3 or <5 years old.

Favorable control rates and relative absence of serious toxicity have established carboplatin and vincristine as the “standard” first-line chemotherapy for low-grade gliomas in younger children (78,80, 81, 82). Carboplatin hypersensitivity occurs over time, often limiting further administration of this regimen (83). Temozolomide, an alkylating agent with modest responsiveness in recurrent low-grade gliomas, is currently in trial with carboplatin/vincristine to try to prolong drug tolerance (84, 85, 86, 87). The five-drug University of California at San Francisco (UCSF) regimen (6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine) has been reported to be similarly efficacious; a randomized trial comparing carboplatin/vincristine to this regimen has been completed in COG, suggesting equal or greater efficacy with the five-drug regimen (79,88). Bevacizumab in combination with irinotecan has been investigated for recurrent low-grade glioma with promising response rates for heavily pretreated patients (89). The decision to proceed with chemotherapy or irradiation relates to patient age and clinical presentation; consideration should involve consultation with and discussion among a multidisciplinary team reviewing
relative risks and benefits with the patient’s family. Factors beyond age alone include symptoms and signs, potential for additional neurocognitive deficits, the likelihood of durable benefit from respective chemotherapeutic regimens, and the radiation volume required in weighing relative potential toxicities. Although not proven to be problematic, there is no confirmation that the response rate and durability of disease control following radiation therapy are independent of prior failure on chemotherapy.

Fusion of MRI with CT imaging is ideal to determine the extent of disease defining the GTV for treatment planning. T1 gadolinium-enhanced imaging may be ideal for JPA; for diffuse astrocytoma (grade II) and the less common low-grade neoplasms, T2-FLAIR or T2 sequences are most useful where the tumor rarely shows contrast enhancement throughout. The CTV may be defined as a 1-cm anatomic expansion; a prospective study at St. Jude indicated a dearth of marginal recurrences with a 1-cm anatomic expansion of the GTV to define the CTV (70,71). Smaller margins may provide adequate control; a 5-mm anatomic expansion is being examined in a prospective COG study. An additional 3-5 mm geometric expansion defines the planning target volume (PTV). The use of small margins requires a careful review of all neuroimaging with great attention to detail including all cystic and solid components of the tumor in the GTV. Similar guidelines appear to be appropriate for grade II (fibrillary) astrocytomas, recognizing that most such tumors in children have readily identifiable margins on imaging; expansion of the GTV by 1 cm has resulted in few marginal failures (70,90). Shrinking fields typically are not used in JPAs; when target volumes for infiltrating fibrillary astrocytomas are used, fields may be reduced to more narrowly encompass the obvious tumor after delivery of 50.4 Gy. For tumors with a cystic component, a CT or limited sequence MRI during radiation therapy may prove useful to evaluate changes in the cystic portion of the tumor during treatment. Diffuse low-grade gliomas can be associated with gliomatosis cerebri or bithalamic astrocytomas; both may be histologically WHO grade II, but the pattern of growth indicates a degree of aggressiveness and infiltration requiring large volume irradiation based on guidelines for malignant gliomas (76,77). For gliomatosis cerebri that is bilateral and involving much of the cerebral hemispheres, corpus callosum, and, sometimes, thalamic nuclei, it may be appropriate to include the whole brain, at least to a dosage level of 40-45 Gy before using a more imaging-defined “boost” volume (77,91).

Astrocytomas with multifocal presentations or subarachnoid seeding generally are treated with craniospinal irradiation (CSI), although the need to cover the entire neuraxis is controversial and unproven (31,40,41).

There is little definitive dose-response data specific for pediatric astrocytomas. Shaw et al. showed an advantage with radiation therapy in JPA and other low-grade astrocytomas only at doses of greater than 53 Gy (91). It seems ironic that the adult low-grade glioma trials have established no clear benefit for dosage levels greater than 45 Gy (the European Organization for Research and Treatment of Cancer study showed no difference between 45 and 59.4 Gy; the North Central Cancer Treatment Group, Radiation Therapy Oncology Group, and Eastern Cooperative Oncology Group study showed no difference between 50.4 and 64.8 Gy) (92,93). Pediatric national trials continue to use doses approaching the established tolerance of critical CNS structures (i.e., 50-54 Gy). The primary justification is the long-term disease control rates documented in studies of pediatric JPA and other low-grade astrocytomas. For children younger than 5 years, a delay in irradiation is appropriate as clinical signs permit, particularly with increasing data indicating the efficacy of chemotherapy in delaying irradiation for an average of 3-5 years. When radiation therapy is needed, a dose of 50-54 Gy with optimal conformality is standard-the same dose level recommended throughout the pediatric age range (70,71).

Ideal techniques achieve close conformation of the high-dose region to a well-defined local target volume. The 3D conformal or intensity-modulated photon irradiation or proton beam radiation therapy can achieve such conformality, with potential differences in sparing adjacent dose-limiting structures (e.g., optic chiasm, eye, and pituitary-hypothalamic region) and in intralesional homogeneity. Given the nature of low-grade gliomas and recognized dose-related toxicities, attention to dose volume histograms (DVH) and a 3D image-based radiation plan is critical in designing treatment techniques. Multiple fields, based on single-plane or non-coplanar techniques, may be used to achieve a dose distribution maximally conformed to the target volume (Fig. 3.5). The impact of low-dose irradiation on broader regions of the developing brain has not yet been fully explored; dose-volume modeling suggests correlations between low dose volumes and cognitive deficits (94). Early results suggest that 3D conformal techniques achieve greater sparing of neuropsychological function, for example, than past experience has shown for conventional therapies (95). The physical properties of protons allow for further reduction in the amount of brain exposed to low-dose irradiation (96,97) (Fig. 3.6). The greater conformality of 3D conformal radiation therapy, intensity-modulated radiotherapy (IMRT), and proton therapy are likely to be associated with less pronounced late toxicities as a result of diminished high-dose exposure of normal tissues (96,98, 99, 100, 101, 102).

The use of single-fraction radiosurgery for primary management of pediatric low-grade gliomas has been reported in several small institutional series (103,104). There are less data to understand the potential risks and benefits of this approach; however, in the rare instances where small lesions distant from critical structures can be targeted, especially in children with NF1 where subsequent development of additional CNS tumors is relatively common, data suggest reasonable efficacy and intermediate-term tolerance (103, 104, 105).

Surgery has been the preferred treatment for unilateral tumors of the optic nerve (115,116,119). Observation may be selected, especially if there is residual vision associated with a lesion confined to the intraorbital optic nerve. Alvord and Lofton (115) reported progression in 70% of children with untreated lesions within 6 years of diagnosis, although it was rarely associated with tumor-related mortality. Most series indicate more indolent, perhaps truly hamartomatous behavior in children with neurofibromatosis (119,121).

For lesions involving the optic chiasm, there are limited data suggesting a role for surgical resection. Decompression or limited resection may be successful in restoring vision (62,63,125). Series from the Hospital for Sick Children, Toronto, and New York University suggest a somewhat broader role for local excision in selected presentations. The latter authors indicate removal of lesions of partially infiltrating low-grade optic pathway astrocytomas with surprisingly little added visual compromise; approximately 50% of such cases have remained stable without further intervention for 3-5 years (60,63,119,125). Whether less aggressive surgery or observation would have achieved similar results relates to the selection of cases for surgery, a debate in the surgical community (8). Care should be taken to avoid visual compromise or other surgical complications as alternative therapies are quite successful.

Typical chiasmatic lesions that involve components of the visual pathways beyond the optic chiasm and hypothalamic region (i.e., with imaging extension to the optic nerves, optic tracts, or optic radiation) may be managed without biopsy confirmation. Most of these tumors are low-grade astrocytomas and most often can be managed based on the clinical and imaging diagnosis. Globular tumors that involve the chiasm and hypothalamus are best biopsied if this can be performed safely; a small percentage of these lesions may be GCTs, unusual types of low-grade neoplasms, or more aggressive malignant gliomas (62,69).

Irradiation is indicated for significant visual or neurologic deficits at presentation or documented progression by clinical evaluation or neuroimaging after observation, surgery, or chemotherapy (13,61,78,81,82,115). Radiation therapy is highly effective for OPTs: 10-year progression-free survival rates exceed 80% (13,68,69,126). Although overall survival at 10 years is unaffected by the initial therapeutic approach (i.e., observation, resection, chemotherapy, or irradiation), progression-free survival rates at 5 and 10 years are substantially higher after radiation therapy (9,13,55). Serial imaging studies document significant tumor response in more than 50% of children after irradiation (69,113). Transient postirradiation tumor enlargement, often in the setting of central cystic degeneration, has been well documented (68). Close observation and medical management (i.e., steroids) rather than aggressive intervention for presumed tumor progression is advised, particularly for lesions that may appear to progress within 6-12 months after radiation (68). Visual improvement has been reported in 25-35% of children after irradiation (68,113,126). Visual deterioration is reported in 10-20% of children after irradiation, largely related to cystic degeneration (and consequent increased mass effect at the chiasm) or unrecognized elevated intracranial pressure (13,68,113,126). Vision should be monitored closely during the radiation course and in the months following completion.

Balancing the indications for radiation therapy and the timing requires judgment and, often, serial evaluations to determine the nature of the disease process. OPTs are associated
with unique late radiation-related sequelae. The young age at diagnosis, central location, and often extensive anatomic involvement challenge the ability to deliver adequate radiation therapy while preserving neurocognitive function; the problem is further accentuated in children with NF1, itself associated with cognitive delays (69,81,113,118). There is also concern about late vascular events: the incidence of occlusive vasculopathy at the circle of Willis in children with brain tumors is highest among those with OPTs, especially in younger children (69,81,127,128). Moyamoya syndrome is characterized by obliteration of the major vessels at the circle of Willis; incomplete brain perfusion is provided by collaterals and peripheral meningeal vessels. The syndrome has been noted after irradiation, perhaps related to cicatricial constriction of vessels tracking through chiasmal and hypothalamic gliomas. An incidence approaching 18% has been reported, especially noted among children less than 2-3 years and those with NF1 (69,127). A baseline MRA prior to irradiation to document vascular status is important, often revealing occult vascular compromise due to the tumor itself; the baseline is important to more easily detect changes after treatment. There is also a heightened concern regarding the risk of second malignancy in patients with NF1 (129,130). The Toronto group has uniquely reported a 10% incidence of second malignant neoplasms after irradiation for OPTs; of interest, a series from Children’s Hospital of Los Angeles showed the same rate of anaplastic degeneration in JPA after surgery alone (112, 121,131).

Because of the radiation-associated morbidities in young children with OPT, Packer et al. (132) explored primary chemotherapy in children younger than 5 years. Initial experience with actinomycin D and vincristine resulted in stabilization in a majority of children and objective tumor reduction in approximately 25%. Although more than 60% of children needed irradiation by 5 years after diagnosis, the approach resulted in a substantial delay in radiation therapy, with a median time to progression of 3 years (132). Subsequent experience with an 18-month regimen of carboplatin and vincristine for low-grade gliomas including those of the hypothalamic region and OPTs has shown a significant rate of objective tumor reduction (reporting greater than 50% tumor reduction in one third of patients), early progression in only 10%, and 3-year progression-free survival that ranges from 75% for children younger than 5 years to 39% for those older than 5 years (78,81). Similar results have been reported with the UCSF five-drug regimen (88). Children with low-grade gliomas of this location are included on the recent and current COG studies discussed earlier in this chapter.

Early experience suggests favorable outcome with secondary irradiation after progression during or after chemotherapy; recent observations related to the timing of initiating radiation therapy suggest that long-term disease control and function are not diminished with prolonged preirradiation intervals (13,78,113). Toxicity with carboplatin and vincristine has been limited, and early data suggest continued intellectual development during chemotherapy (81). There is a balance between duration of disease control (clearly superior with radiation therapy) and less durable control with chemotherapy apparently without the serious morbidities associated with irradiation in the younger age group (13,113,124). In current practice, most children below 5-10 years receive chemotherapy as the initial intervention, with some centers extending this to all prepubertal children. It is important not to avoid irradiation even in younger children when progressive visual loss is apparent despite chemotherapy.

The volume of disease can be quite variable for OPTs. The target volume includes only the radiographically involved aspects of the optic pathway. MRI has enhanced the ability to better define segments of the optic pathway that are involved. Tumors are often confined to the suprasellar region for lesions that are limited to the chiasm with or without hypothalamic involvement. Central lesions necessitate multifield, often noncoplanar arrangements to optimize 3D conformal approaches, limiting the dosage to the surrounding cerebral hemispheres and minimizing intralesional inhomogeneity of dose (71,100). Proton radiation therapy provides a dosimetric benefit for such tumors (101). Optic nerve involvement, most often in NF1, necessitates inclusion of the nerve to the posterior aspect of the globe in defining the target volume. For lesions extending along the optic tracts or beyond (occasionally to involve the optic radiation, toward or to the occipital lobes), it is key to discern where apparent neoplastic changes differ from edema (68,118).

The extensive literature on radiation therapy for OPTs typically calls for dosage levels of 50-54 Gy, most often at 180 cGy per fraction (68,116,121,126). Reduction to 50 Gy at 150 cGy daily may be appropriate in children younger than 3 years (9,126).